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GSK3 Controls Migration of the Neural Crest Lineage

Sandra G Gonzalez Malagon, Anna Lopez Munoz, Daniel Doro, Triona Bolger, Evan Poon, Elizabeth Tucker, Hadeel Adel Al-Lami, Matthias Krause, Christopher Phiel, Louis Chesler, Karen J Liu

Preprint posted on May 01, 2018 http://dx.doi.org/10.1101/243170

ALK-mediated GSK3 phosphorylation is a conserved mechanism that regulates neural crest migration in development and a possible key to aberrant migration in neuoroblastoma.

Selected by Amanda Haage

Categories: cell biology, neuroscience

Why This Is Cool –Neural crest migration is critical for proper development, but aberrant migration of these cells can also contribute to many cancers, such as neuroblastoma. Despite the obvious importance, mechanisms underlying neural crest migration are relatively unknown due to the technical difficulty of studying these cells in vivo. Through the use of an ex vivo culture system, as well as both genetic and pharmalogical inhibition, the authors show a novel requirement of GSK3 tyrosine phosphorylation (pY-GSK3) for proper neural crest migration. They demonstrate the requirement for pY-GSK3 across two different species (mouse and frog), providing excellent support for the argument of a conserved and general regulatory mechanism. They go on to show that loss of GSK3 results in specific defects to the cytoskeleton, mainly changes to the stability and localization of known players (actin, microtubules, FAK, Rac1, cdc42). This demonstrates how the migration machinery may be regulated by pY-GSK3. They then investigate the upstream effectors, focusing on ALK because of its known association with neuroblastoma. ALK is shown to be in the right place at the right time and loss of ALK phenocopies loss of pY-GSK3 in the neural crest. Lastly, they end with drawing similar conclusions in neuroblastoma cell lines, demonstrating how this general mechanism for regulating neural crest cell migration could become deregulated in neural crest derived cancers.

Why I Selected It –  I’m specifically interested in using the ex vivo culture system of neural plates, described here, for my own work. They have presented an excellent characterization of the migration and polarity of the mammalian neural crest, a difficult to isolate primary cell population.

Fig 1 – (I) Transverse cranial section of E9 mouse showing immunoflourescent staining for Hoechst/DNA (blue), pY-GSK3 (green) and p75NTR (neural crest, red). (J) Schematic of E8.5 mouse embryo depicting cranial neural crest (CNC) dissection.

 

Open Questions – 

  • How does GSK3 exert effects on FAK and the cytoskeleton? Is it known to bind directly to any of these players? What could mediate this interaction and the outcomes presented here?
  • Are similar mechanisms required in other neural crest populations? Here they focus on the outcomes for craniofacial development, but what about melanocytes or cardiac neural crest cells?

Related Research- 

  • Direct previous study by this group
    • Liu, K. J., Arron, J. R., Stankunas, K., Crabtree, G. R. & Longaker, M. T. Chemical rescue of clef palate and midline defects in conditional GSK-3beta mice. Nature 446, 79–82, https://doi.org/10.1038/nature05557 (2007).
  • GSK3 & cell migration
  • ALK & neuroblastoma

 

Posted on: 30th January 2018 , updated on: 26th February 2018

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